The overall goal of the proposed research is to contribute to an understanding of the role of hepatitis B virus (HBV) and other factors in the pathogenesis of primary hepatocellular carcinoma (PHC). The ultimate objective is to prevent or delay the onset of PHC and chronic liver disease (CLD) in carriers of HBV. In Project I the effect of early diagnosis and treatment on the outcome of PHC will be determined. In Project II risk factors related to responses to HBV and other factors in infected individuals will be determined. In Project III we will study the effect of a plant derived medication on the development of PHC in woodchucks infected with woodchuck hepatitis virus. Project IV is a study of the effect of this medication on replicating forms of duck hepatitis B virus. Project V is a study of genetic mechanisms associated with the development of PHC in human HBV carriers. Project VI will lead to the development of new statistical methods for relative risk regression models. There is a Core structure to support these projects.